Biology subjects

Klotz, S.

Publications and source records attributed to Klotz, S..

3 recordsLinked to original sources

bioRxiv2025

Distinct cerebrospinal fluid DNA methylation signatures linked to Alzheimer's disease

Alzheimers disease (AD) accounts for more than 60% of the dementia cases and currently there is no curative treatment for it. With the emergence of potentially disease modifying treatments, early diagnosis is key to identify patient groups that would benefit from such treatments, aiming to prevent severe cognitive decline. We previously identified a set of DNA methylation signatures that allow for accurate diagnosis of AD in cortical neurons and brain tissue, even before clinical manifestation of the disease [1]. Here we investigate 11 of these signature regions via targeted next-generation sequencing in cell-free DNA (cfDNA) isolated from cerebrospinal fluid (CSF) of AD patients homozygous for APOE4 (n=4) and sporadic AD (n=5) cases compared to age-matched control samples (n=5). Our analyses demonstrated that 6/11 of the tested DNA methylation signatures that had initially been identified in cortical neurons and brain tissue were also validated in cfDNA. The remainder of the tested regions either showed opposite trends (3/11) or did not result in any differences (2/11) between control and AD cases. Thus, this presents a direct approach allowing to test for these DNA methylation signatures in CSF-derived cfDNA, and bypasses the need to generate induced pluripotent stem cell-derived cortical neurons from patients.

neuroscience↗

bioRxiv2024

Evidence for low affinity of GABA at the vesicular monoamine transporter VMAT2. Implications for transmitter co-release from dopamine neurons

Background and PurposeMidbrain dopamine (DA) neurons comprise a heterogeneous population of cells. For instance, some DA neurons express the vesicular glutamate transporter VGLUT2 allowing these cells to co-release DA and glutamate. Additionally, GABA may be co-released from DA neurons. However, most cells do not express the canonical machinery to synthesize GABA or the vesicular GABA transporter VGAT. Instead, GABA seems to be taken up into DA neurons by a plasmalemmal GABA transporter (GAT1) and stored in synaptic vesicles via the vesicular monoamine transporter VMAT2. Yet, it remains unclear whether GABA indeed interacts with VMAT2, or whether another transmitter could be responsible for the observed inhibitory effects attributed to GABA. Experimental ApproachWe used radiotracer flux measurements in VMAT2 expressing HEK-293 cells and synaptic vesicles from rodents to determine whether GABA qualifies as substrate at VMAT2. mRNA in situ hybridization was employed to determine expression of VMAT2 and GAT1 transcripts in DA neurons of mouse and in human midbrains. Key ResultsWe found that GABA reduced uptake of VMAT2 substrates in rodent synaptic vesicle preparations from striatum and cerebellum at millimolar concentrations but had no effect in VMAT2-expressing cells indicating that key components are missing in a non-neuronal system. Roughly 60 % of murine and human DA neurons in the substantia nigra express VMAT2 and GAT1 suggesting that many may be capable of co-releasing DA and GABA. Conclusion and ImplicationOur experiments suggest that GABA is a low-affinity substrate at VMAT2 with potential implications for basal ganglia physiology and disease. Bullet point summaryO_ST_ABSWhat is already knownC_ST_ABSO_LISubpopulations of dopamine neurons co-release glutamate and/or GABA. C_LIO_LIWhile glutamate is loaded into vesicles by VGLUT2, GABA co-release depends on GAT1 and VMAT2. C_LI What this study addsO_LIThe relative affinity of GABA at VMAT2 was found to be in the millimolar range. C_LIO_LIHuman midbrain dopamine neurons express GAT1. C_LI Clinical significanceO_LIGABA co-release from midbrain dopamine neurons may also occur in humans. C_LIO_LIGABA co-release from dopamine neurons may play a role in neuropsychiatric diseases C_LI

neuroscience↗

bioRxiv2019

Resilience trinity: safeguarding ecosystem services across three different time horizons and decision contexts

Ensuring ecosystem resilience is an intuitive approach to safeguard future provisioning of ecosystem services (ES). However, resilience is an ambiguous concept and difficult to operationalize. Focusing on resilience mechanisms, such as diversity, network architectures or adaptive capacity, has recently been suggested as means to operationalize resilience. Still, the focus on mechanisms is not specific enough because the usefulness of a mechanism is context-dependent. We suggest a conceptual framework, resilience trinity, to facilitate management of resilience mechanisms in three distinctive decision contexts and time-horizons. i) reactive, when there is an imminent threat to ES resilience and a high pressure to act, ii) adjustive, when the threat is known in general but there is still time to adapt management, and iii) provident when time horizons are very long and the nature of the threats is uncertain, leading to a low willingness to act. This emphasizes that resilience has different interpretations and implications at different time horizons which however need to be reconciled. The inclusion of time into resilience thinking ensures that longer-term management actions are not missed while urgent threats to ES are given priority.

ecology↗